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A33 Differences in bioenergetic status in patient-derived fibroblast cells are associated with age of onset in huntington disease
  1. Sarah L Gardiner1,2,
  2. Chiara Milanese3,
  3. Merel W Boogaard4,
  4. Ronald AM Buijsen2,
  5. Marye Hogenboom1,
  6. Raymund AC Roos1,
  7. Pier G Mastroberardino3,
  8. Willeke MC van Roon-Mom2,
  9. N Ahmad Aziz1,5
  1. 1Departments of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
  2. 2Human Genetic, Leiden University Medical Centre, Leiden, The Netherlands
  3. 3Department of Molecular Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
  4. 4Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  5. 5Population Health, German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany

Abstract

Background Mutant CAG repeat size is the lead determinant of age of onset in Huntington disease. Nevertheless, a substantial proportion of variation in age of onset in Huntington disease remains unexplained. Accumulating evidence suggests that bioenergetic defects play a central role in Huntington disease pathology, but to what extent these impairments influence symptom onset independently from the mutant CAG repeat size is unknown.

Methods Using the Leiden Huntington disease database, we selected nine pairs of Huntington disease patients matched for mutant CAG repeat size and sex, but with a difference of at least ten years in age of onset. From skin biopsies we isolated fibroblasts in which we 1) quantified the ATP concentration before and after a hydrogen-peroxide challenge and 2) measured mitochondrial respiration and glycolysis in real-time, using the Seahorse XF Extracellular Flux Analyzer XF24.

Results The ATP concentration in fibroblasts was significantly lower in Huntington disease patients with an earlier age of onset, independent of calendar age and disease duration. Maximal respiration, spare capacity, and respiration due to complex II activity, indices of mitochondrial respiration, were significantly lower in Huntington disease patients with an earlier age of onset, again independent of calendar age and disease duration.

Conclusion A less efficient bioenergetic profile was found in fibroblast cells from Huntington disease patients with an earlier age of onset independent of mutant CAG repeat size. Thus, differences in bioenergetics could explain part of the residual variation in age of onset in Huntington disease.

  • Huntington disease
  • age of onset
  • bioenergetic status
  • fibroblasts

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